DNA as the substance of genes is regulated by various factors, and expression of its genetic information is controlled thereby. For example, transcription of genetic information from DNA to RNA is controlled by a plurality of DNA binding proteins which recognizes several to scores of nucleotide sequences on the gene and bind thereto. NF-.kappa.B (nuclear factor-.kappa.B) known as one of such DNA binding proteins is present in the nuclear extract of B cells which are antibody-producing cells and has been identified as a factor that binds to the enhancer of immunoglobulin .kappa. chain (Ig.kappa.) gene. With the progress of studies on this factor, it has been revealed that this is a transcription factor which takes part in the expression induction of a large number of genes that are induced by stimulation and is broadly concerned in the regulation of vital phenomenon.
This NF-.kappa.B is generally present in the cytoplasm in the form of a complex in which its homodimer of proteins having a molecular weight of 50 kD or its heterodimer of a protein of 50 kD in molecular weight and a protein of 65 kD in molecular weight is bonded to a protein called I-.kappa.B which inhibits activity of the dimer. When a certain stimulation is given to the cells, I-.kappa.B is modified and released from the complex to cause activation of NF-.kappa.B, so that the dimer is transferred into the nucleus and its DNA binding activity becomes detectable. It is known that this activity is generated as a result of direct activation, not mediated by the expression of other genes such as second messengers and the like.
In addition, the NF-.kappa.B binding sequence on DNA has been found in various genes and it has been shown that it is actually important for the expression of the function of genes. The binding sequence of NF-.kappa.B (.kappa.B motif) is composed of about 10 bases having a common sequence which starts with a cluster of G (guanine) and ends with a cluster of C (cytosine) (consensus sequence 5'-GGGRNNYCCC-3')(SEQ ID NO:1. However, a number of sequences to which DNA binding proteins can be bonded are present on the genes of interleukin-1 (to be referred to as IL-1 hereinafter in some cases) and tumor necrosis factor (to be referred to as TNF hereinafter in some cases) which are known as inflammatory proteins, and it is known that the NF-.kappa.B binding sequence is also present therein (Clark, B. D. et al., Nucl. Acids Res., 14, 7898, 1984; Nedospasov, S. A. et al., Cold Spring Harb. Symp. Quant. Biol., 51, 611, 1986). Actually, it has been reported that the binding of NF-.kappa.B inhibits transcription to mRNA (Hiscott, J. et al., Mol. Cell. Biol., 13, 6231, 1993; Collart, M. A. et al., Mol. Cell. Biol., 10, 1498, 1990).
As a substance which inhibits the transcription factor of NF-.kappa.B, an NF-.kappa.B binding protein has been disclosed in European Patent 584238.
In addition, it has been reported that a composition which contains an alkaloid originated from a plant belonging to the genus Stephania of the family Menspermaceae, as its active ingredient, inhibits production of TNF.alpha., interleukin-6 (to be referred to as IL-6 hereinafter in some cases) and interleukin-8 (to be referred to as IL-8 hereinafter in some cases) (JP-A-8-301761, the term "JP-A" as used herein means an "unexamined published Japanese patent application").
Phospholipid which constitutes the biological membrane releases arachidonic acid by the action of phospholipase A.sub.2. Leukotriene, thromboxane, prostaglandine and the like are produced from the arachidonic acid by the action of 5-lipoxygenase or cyclooxygenase. These substances exert complex physiological activities and take important roles in the maintenance and regulation of the living body. In the living body, various cytokines are released by receiving various types of stimulation and cause inflammatory reactions. The prior art drugs inhibit expression of histamine and leukotriene B4 or prostaglandine E2 or the like inflammatory protein by the antagonism on mediator receptors of histamine and the like or by the inhibition of lipoxygenase, cyclooxygenase and the like metabolic enzymes in the arachidonic acid cascade. However, effects of non-steroidal drugs are expected for only symptomatic therapy and not sufficient as radical therapy, while steroid drugs are effective but have a problem in that they cannot be administered for a prolonged period of time due to their strong side effects. Particularly, autoimmune disease and the like inflammatory diseases become chronic in many cases and therefore require prolonged medical treatments, so that drugs having side effects are not applicable to such diseases. In addition, NF-.kappa.B takes an important role in the replication of HIV-1, so that search for a substance capable of inhibiting NF-.kappa.B activity is expected for not only its anti-inflammatory effects but also inhibition of acquired immunodeficiency syndrome (AIDS and the like) by its effect to inhibit transcription of long terminal repeat (LTR) of HIV-1, namely replication of the virus.